Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD); however, the development of COPD is markedly variable among smokers, and genetic factors likely influence this variability. Candidate gene association studies have identified several potential COPD susceptibility genes, and genome-wide association studies promise to confirm multiple COPD susceptibility loci. However, association studies typically do not identify the functional variants in associated genes. Moreover, rare variants may contribute to COPD susceptibility, and association studies of attainable sample sizes cannot assess their impact. In the Boston Early-Onset COPD Study, positional cloning efforts have localized several potential COPD susceptibility loci, and rare variant analysis in this study has identified a potentially functional variant in elastin which may influence COPD susceptibility. In order to identify both rare and common genetic variants influencing COPD susceptibility, we will perform dense resequencing of 10 candidate genes identified from previous and ongoing genetic association studies. To characterize the genetic variation of these candidate genes comprehensively, resequencing of the complete genomic sequence of these 10 genes will be performed in three sets of case-control subjects: A) 180 severe, early-onset COPD probands and 180 of their smoking relatives with normal FEV1 values; b) 200 National Emphysema Treatment Trial (NETT) COPD cases and 200 Normative Aging Study (NAS) smoking control subjects; and 200 International COPD Genetics Network (ICGN) COPD cases and 200 ICGN smoking control subjects. Rare variant analysis will be performed by comparing the frequency of non-synonymous SNPs in COPD cases and controls. Common variants will be tested for genetic association in five populations: A) NETT cases and NAS controls; b) two sets of Boston Early-Onset COPD Study families; c) ICGN families; and d) African-American COPD cases and controls. Potentially functional rare and common variants will be tested for their effects on gene expression in lymphoblastoid cell lines of early-onset COPD probands by comparing heteronuclear RNA (pre- mRNA) levels across genotypes and by performing allelic imbalance expression analysis. If novel COPD susceptibility genes can be found, new pharmacological interventions for COPD could be developed, improved understanding of COPD pathophysiology could result, and susceptible individuals could be identified. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is likely influenced by genetic factors, but the only proven genetic determinant of COPD is severe alpha 1-antitrypsin (AAT) deficiency. In order to identify novel common and rare genetic determinants of COPD, resequencing potential susceptibility genes in large numbers of COPD and control subjects will be performed. Genetic association studies of common variants will be undertaken in multiple populations, and functional studies of identified variants will be performed.